N-(pyrrol-1-yl)pyridinamine compounds having enhancing activity

ABSTRACT

There are disclosed novel compounds of the formula ##STR1## where R is H, loweralkyl, halogen, cyano, loweralkanoyl, arylloweralkanoyl, aroyl, --CH(OH)r 1 , --C(OH)r 1  r 2  or --CH 2  Or 2 , where r 1  is H, loweralkyl, arylloweralkyl or aryl and r 2  is loweralkyl; R 1  H, loweralkyl, arylloweralkyl, phenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl, aminophenyl, loweralkanoylaminophenyl, loweralkoxycarbonyl, arylloweralkylkoxycarbonyl, aryloxycarbonyl, loweralkylaminocarbonyl, arylloweralkylaminocarbonyl, arylaminocarbonyl, alkanoyl, arylloweralkanoyl, aroyl, alkenoyl or alkynoyl; and R 2  is H, NO 2 , NH 2 , halogen, loweralkanoylamino, arylloweralkanoylamino, aroylamino or loweralkyl, or R 2  as a whole is a combination of 2, 3 or 4 halogen atoms; or pharmaceutically acceptable acid addition salts thereof, which are useful for enhancing memory, methods for synthesizing them, pharmaceutical compositions comprising an effective memory enhancing amount of such a compound and methods of treating a patient in need of memory enhancement by administering such a compound to the patient.

This is a division of prior application, Ser. No. 200,983, filed June 1,1988, now U.S. Pat. No. 4,900,742, which is a division of priorapplication Ser. No. 804,430, filed Dec. 4, 1985, now U.S. Pat. No.4,752,610.

This invention relates to novel compounds of the formula ##STR2## whereR is H, loweralkyl, halogen, cyano, loweralkanoyl, arylloweralkanoyl,aroyl, --CH(OH)r₁, --C(OH)r₁ r₂ or --CH₂ Or₂, where r₁ is H, loweralkyl,arylloweralkyl or aryl and r₂ is loweralkyl; R₁ is H, loweralkyl,arylloweralkyl, phenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl,aminophenyl, loweralkanoylaminophenyl, loweralkoxycarbonyl,arylloweralkoxycarbonyl, aryloxycarbonyl, loweralkylaminocarbonyl,arylloweralkylaminocarbonyl, arylaminocarbonyl, alkanoyl,arylloweralkanoyl, aroyl, alkenoyl or alkynoyl; and R₂ is H, NO₂, NH₂,halogen, loweralkanoylamino, arylloweralkanoylamino, aroylamino orloweralkyl, or R₂ as a whole is a combination of 2, 3 or 4 halogenatoms; or pharmaceutically acceptable acid addition salts thereof, whichare useful for enhancing memory, methods for synthesizing them,pharmaceutical compositions comprising an effective memory enhancingamount of such a compound and methods of treating a patient in need ofmemory enhancement by administering such a compound to the patient.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical, and geometricalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following general rules of terminology shall apply throughout thespecification and the appended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkyl include methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chainpentyl and hexyl.

Unless otherwise stated or indicated, the term loweralkoxy denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup having 0, 1, 2 or 3 substituents each of which being independentlyloweralkyl, loweralkoxy, halogen, CF₃, NO₂ or CN.

Unless otherwise stated or indicated, the term alkyl shall mean asaturated hydrocarbon group of 1 to 20 carbon atoms, the term alkenylshall mean a hydrocarbon group of 1-20 carbon atoms having one or morecarbon-carbon double bonds, and the term alkynyl shall mean ahydrocarbon group of 1-20 carbon atoms having one or more carbon-carbontriple bonds.

The term loweralkanoic acid shall mean a carboxylic acid in which thecarboxyl group is attached to hydrogen or an alkyl group of from 1 to 5carbon atoms.

The term loweralkanoyl shall mean a group obtained by removing a hydroxygroup from the carboxyl group of a loweralkanoic acid, and thus itincludes for instance formyl, acetyl and the like.

The term arylloweralkanoyl shall mean a loweralkanoyl group having anaryl substituent thereon, the terms loweralkanoyl and aryl having therespective meanings defined above.

The term aroyl shall mean arylcarbonyl, an example being benzoyl.

The term arylloweralkyl shall mean a loweralkyl group having an arylsubstituted thereon, the terms loweralkyl and aryl having the respectivemeanings defined above.

The terms alkanoyl, alkenoyl and alkynoyl shall mean groups obtained byremoving a hydroxy group from the carboxyl group of alkanoic acid,alkenoic acid and alkynoic acid, respectively.

Thus, for instance, linoleyl group derived from linoleic acid is anexample of the term alkenoyl as defined above.

The term acyl shall mean loweralkanoyl or arylloweralkanoyl as definedabove.

The compounds of formula (I) of this invention can be synthesized byfollowing or combining one or more of the steps described below, notnecessarily in the order presented. Throughout the description of thesynthetic steps, the definitions of R, R₁, R₂, r₁ and r₂ are as givenabove unless otherwise stated or indicated, and R₃ through R₁₄ appearingbelow shall have the same meanings defined in their respective firstappearances unless otherwise stated or indicated.

STEP A

A compound of formula (II) where R₃ is H, loweralkyl, halogen or cyanoand R₄ is H, loweralkyl or phenyl is reacted with a compound of formula(III) where X is chlorine or fluorine and R₅ is H, N₂, halogen orloweralkyl to afford a compound of formula (IV). ##STR3## Said reactionis typically conducted in an ethereal solvent such asbis(2-methoxyethyl)ether, diethyl ether, dimethoxy ether, dioxane ortetrahydrofuran or polar aprotic solvent such as dimethylformamide,dimethylacetamide, hexamethylphosphoramide or dimethylsulfoxide at atemperature of between about 20° C. and 150° C.

STEP B

As an alternative to STEP A, when R₃ is H or loweralkyl, compound IV canbe obtained by reacting a compound of formula (V) with a compound offormula (VI). ##STR4## Said reaction is typically conducted in analkanoic acid such as glacial acetic acid, propanoic acid or formic acidat a temperature of about 80°-120° C.

STEP C

A compound of formula IVa is treated with a strong base such as sodiumhydride in a solvent such as dimethylformamide or dimethylsulfoxide at atemperature of between about 0° and 5° C. to form the anion of IVa,which is reacted with a loweralkyl or arylloweralkyl halide of formulaR₆ --X, where R₆ is loweralkyl or arylloweralkyl and X is Cl, Br or I ata temperature of between about 0° and 25° C. ##STR5##

STEP D

The anion of IVa, prepared as in STEP C, is reacted withfluoro-nitrobenzene, cyano-fluorobenzene orfluoro-trifluoro-methylbenzene of formula ##STR6## where Y is nitro,cyano, trifluoromethyl to afford a compound of formula (VIII) below.##STR7## Said reaction is typically conducted in a suitable solvent suchas dimethylformamide or dimethylsulfoxide at a temperature of betweenabout 0° and 120° C.

STEP E

Compound IVa is reacted with a loweralkyl isocyanate, arylloweralkylisocyanate or aryl isocyanate of formula R₇ NCO where R₇ is loweralkyl,arylloweralkyl or aryl to afford a compound of formula (IX). ##STR8##Said reaction is typically conducted in a suitable solvent such asaromatic hydrocarbon including benzene, toluene or the like at atemperature of about 30°-60° C.

STEP E

Compound IVa is reacted with a loweralkyl chloroformate, arylloweralkylchloroformate or aryl chloroformate of formula Cl--CO--OR₇ to afford acompound of formula (X). ##STR9## Said reaction is typically conductedin a suitable solvent such as dichloromethane at a temperature of about20°-50° C.

STEP G

Compound IVa is reacted with an alkanoyl chloride, arylloweralkanoylchloride, aroyl chloride, alkenoyl chloride or alkynoyl chloride offormula (XI) where R₈ is alkyl, aryllowerlkyl, aryl, alkenyl or alkynylto afford a compound of formula (XII). ##STR10## Said reaction istypically conducted in a suitable solvent such as dichloromethane at atemperature of 20°-50° C.

Where the compound R₈ COCl is not commercially available, it is preparedfrom the corresponding carboxylic acid R₈ COOH and thionyl chloride in asuitable solvent, for instance, in benzene at the reflux temperature.

STEP H

As an alternative to STEP A or B, a compound of formula (IVb) where R₉is loweralkyl can be prepared by reacting compound IVa with a strongbase such as sodium hydride and then reacting the product with adiloweralkyl sulfate of the formula (R₉)₂ SO₄. ##STR11## Said first stepis conducted typically in a suitable medium such as dimethylformamide atice temperature. After the first step is complete, the second step isconducted by adding a solution of (R₉)₂ S₄ in a suitable solvent such asdimethylformamide to the mixture obtained from the first step andstirring the resultant mixture at a temperature of about 20°-50° C.

STEP I

As an alternative to the foregoing steps, a compound of formula (XIII)where R₁₀ is loweralkyl, arylloweralkyl, aryl, loweralkoxycarbonyl,arylloweralkoxycarbonyl, aryloxycarbonyl, alkanoyl, arylloweralkanoyl oraroyl can be prepared by reacting a compound of formula (XIV) withN-chlorosuccinimide (NCS). ##STR12## Said chlorination is conductedtypically in a suitable solvent such as tetrahydrofuran at a temperatureof about 20°-60° C.

STEP J

A compound of formula (XV) where R₁ is loweralkyl, loweralkoxycarbonyl,alkanoyl, alkenoyl, alkynoyl, arylloweralkanoyl or aroyl, and R₂ is H,NO₂, halogen or loweralkyl or R₂ as a whole is a combination of 2, 3 or4 halogen atoms which is prepared by use of one or more of the reactionsteps described in this specification is reacted with phosphorusoxychloride and dimethylformamide to afford a compound of formula (XVI).##STR13## Said reaction is typically conducted in a suitable solventsuch as 1,2-dichloroethane at a temperature of about 70°-85° C.

STEP K

A compound of formula (XVa) where R₁ is loweralkyl, loweralkoxycarbonyl,alkanoyl, alkenoyl, alkynoyl, arylloweralkanoyl or aroyl and R₁₁ is H,NO₂, halogen or loweralkyl is reacted with a loweralkanoyl chloride,arylloweralkanoyl chloride or aroyl chloride of formula R₇ COCl in thepresence of zinc chloride to afford a compound of formula (XVII).##STR14## Said reaction is typically conducted in a suitable solventsuch as dichloroethane at a temperature of about 20°-60° C.

STEP L

A compound of formula XVIII below where r₁ is hydrogen, loweralkyl,arylloweralkyl or aryl as defined earlier and R₁₂ is H, halogen orloweralkyl is reduced to a compound of formula XIX below with NaBH₄ orLiAlH₄. ##STR15## When NaBH₄ is used, said reduction is conductedtypically in a lower aliphatic alcohol such as isopropanol or ethanol ata temperature of about 0°-30° C. and thereafter adding water to thereaction mixture. When LiAlH₄ is used, said reduction is conductedtypically in an ethereal solvent such as tetrahydrofuran or ether at atemperature of about 0°-30° C. and thereafter adding water to thereaction mixture.

STEP M

Compound XVIII is reacted with a Grignard reagent of the formula r₂ MgBr(where r₂ is loweralkyl as defined earlier) and the product isthereafter hydrolyzed to afford a compound of formula (XX) below.##STR16##

STEP N

A compound of formula (XXI) where R₁ is H, loweralkyl, arylloweralkyl,phenyl, cyanophenyl, trifluoromethylphenyl, loweralkoxycarbonyl,aryloxycarbonyl, loweralkylaminocarbonyl, arylloweralkylaminocarbonyl,arylaminocarbonyl, alkanoyl, arylloweralkanoyl, aroyl, alkenoyl oralkynoyl which is prepared by use of one or more of the reaction stepsdescribed in this specification is catalytically hydrogenated withhydrogen gas and a suitable catalyst such as palladium on carbon toafford a compound of formula (XXII). ##STR17##

Said hydrogenation is typically conducted in a suitable solvent such asethyl acetate, isopropanol, ethanol or methanol at the ambienttemperature.

STEP O

As an alternative to the foregoing steps, compound IVa can be preparedby hydrolyzing compound X. (Needless to say, the purpose of STEP O isnot to reverse aforementioned STEP F in order to regain the startingcompound of STEP F. Said STEP O can be useful, for instance, for thepurpose of converting R₃ in formula IVa from hydrogen to 2-chloro. Thus,for this purpose, one can first convert the amino hydrogen in formulaIVa to ethoxycarbonyl by use of STEP F and then introduce chlorine intothe 2-position of the pyrrole ring by use of STEP I, and thereafterhydrolyze the resultant product by use of STEP O, instead of conductingthe N-chlorosuccinimide reaction directly with compound IVa. Similarly,STEP O can also be useful for introducing the group --COR₇ into thepyrrole ring according to STEP K above or the group CHO according toSTEP J when R₁ is hydrogen.

    (X)+H.sub.2 O→(IVa)

Said hydrolysis is conducted typically by stirring a mixture comprisingcompound X, an alkali such as NaOH and a suitable medium such as ethanolplus water at a temperature of about 70°-100° C.

STEP P

A compound of formula (XXIIa) where R₁ is loweralkyl, arylloweralkyl,phenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl,loweralkoxycarbonyl, aryloxycarbonyl, loweralkylaminocarbonyl,arylloweralkylaminocarbonyl, arylaminocarbonyl, alkanoyl,arylloweralkanoyl, aroyl, alkenoyl or alkynoyl is reacted with phenylformate to afford a compound of formula (XXIII) ##STR18## Typically saidreaction is conducted by stirring a solution of compound XXIIa in excessphenyl formate at a temperature of about 20°-50° C.

STEP Q

Compound XXIIa where R₁ is loweralkyl, arylloweralkyl, phenyl,nitrophenyl, cyanophenyl, trifluoromethylphenyl, loweralkoxycarbonyl,aryloxycarbonyl, lowerlakylaminocarbonyl, arylloweralkylaminocarbonyl,arylaminocarbonyl, alkanoyl, arylloweralkanoyl, aroyl, alkenoyl oralkynoyl is reacted with an acyl chloride of formula R₁ COCl to afford acompound of formula XXIV. ##STR19## Said reaction is typically conductedin a suitable solvent such as dichloromethane in the presence oftriethylamine at a temperature of about 0°-25° C.

STEP R

As an alternative to the foregoing steps, a compound of formula (XXV)where R is H or loweralkyl, and R₁ is loweralkyl, arylloweralkyl,phenyl, nitrophenyl, or trifluoromethylphenyl, can be prepared byreacting a compound of formula IVc with a loweralkyl lithium of theformula R₁₃ Li. ##STR20## Said reaction is usually conducted in asuitable solvent such as tetrahydrofuran at a temperature of betweenabout -10° C. and 30° C.

STEP S

A compound of formula (XIXa) below is reacted with a strong base such assodium hydride and the resultant alkoxide anion is reacted with aloweralkyl halide of the formula r₂ X to afford an ether of formula(XXVI) below. Said two-step procedure is conducted in substantially thesame manner as STEP H above. ##STR21##

STEP T

A compound of formula (XXVII) below where m is 2, 3 or 4, each Z isindependently F, Cl, Br or I present on the 2,3, 5 or 6-position of thepyridine ring and R₁₄ is H, loweralkyl or CO₂ C₂ H₅ is prepared byreacting a compound of formula (XXVIII) with a strong base such as NaHand thereafter reacting the resultant anion with a compound of formula(XXIX) below. ##STR22## Said anion formation is typically conducted in asuitable solvent such as dimethylformamide at a temperature of about0°-15° C. After the first step is complete, the second step is conductedtypically by adding a solution of compound (XXIX) in a suitable solventsuch as dimethylformamide, tetrahydrofuran or a mixture thereof to themixture obtained from the first step and stirring the resultant mixtureat about 0°-25° C. STEP T works also when certain groups such as formyl,halogen, loweralkyl are present on the pyrrole ring.

STEP U

Substantially the same hydrogenation technique as described in STEP Ncan be used to hydrogenate a compound of formula XXX below to afford acompound of formula XXXI below. ##STR23##

STEP V

Substantially the same reaction technique as described in STEP P can beused to convert compound XXXI to a compound of formula XXXII below.##STR24##

STEP W

Substantially the same reaction technique as described in STEP Q can beused to convert compound XXXI to a compound of formula XXXIII below.##STR25##

The N-(pyrrol-1-yl)pyridinamine compounds of formula I of the presentinvention are useful in the treatment of various memory dysfunctionscharacterized by decreased cholinergic function, such as Alzheimer'sdisease.

Cholinergic agonists have been shown to have increased affinity for [³H]-QNB (quinuclidinyl benzilate) binding sites in the presence of zincions. Thus, enhanced [³ H]-QNB displacement by a compound in thepresence of zinc is taken as a measure of cholinergic agonist activity,and would therefore be useful in the treatment of Alzheimer's disease.

[³ H]-QNB DISPLACEMENT ASSAY

The ability to displace [³ H]-QNB in the presence and absence of zincions was determined by the method of C. P. Smith and F. P. Huger,Biochemical Pharmacology, 32, 377 (1983).

    ______________________________________                                                                   Ratio                                                         IC.sub.50       W/O Zinc/                                          Compound     W/O Zinc   With Zinc  With Zinc                                  ______________________________________                                        N-(1H-Pyrrol-1-                                                                            3.67 × 10.sup.-4                                                                   3.04 × 10.sup.-5                                                                    12.2                                      yl)-4-pyridin-                                                                amine                                                                         N-Methyl-N-(1H-                                                                            1.42 × 10.sup.-4                                                                   1.32 × 10.sup.-5                                                                    10.7                                      pyrrol-1-yl)-                                                                 4-pyridinamine                                                                1-[N-Methyl-N-                                                                             1.85 × 10.sup.-4                                                                   3.29 × 10.sup.-5                                                                   5.6                                        (4-pyridinyl)]-                                                               aminopyrrol-3-                                                                carboxaldehyde                                                                N-[2-(1-hydroxy-                                                                           1.73 × 10.sup.-4                                                                    2.2 × 10.sup.-5                                                                   7.8                                        ethyl)-1H-pyrrol-                                                             1-yl]-N-methyl-4-                                                             pyridinamine                                                                  N-(2-chloro-1H-                                                                            3.34 × 10.sup.-5                                                                    5.4 × 10.sup.-6                                                                   6.2                                        pyrrol-1-yl)-N-                                                               ethyl-4-                                                                      pyridinamine                                                                  Pilocarpine  5.80 × 10.sup.-6                                                                   1.72 × 10.sup.-6                                                                   3.4                                        (reference compound)                                                          ______________________________________                                    

This utility is further demonstrated by the ability of these compoundsto restore cholinergically deficient memory in the Dark Avoidance Assay,where they are in general active over a broader dose range thanheretofore known compounds, a distinct therapeutic advantage.

Dark Avoidance Assay

In this assay mice are tested for their ability to remember anunpleasant stimulus for a period of 24 hours. A mouse is placed in achamber that contains a dark compartment; a strong incandescent lightdrives it to the dark compartment, where an electric shock isadministered through metal plates on the floor. The animal is removedfrom the testing apparatus and tested again, 24 hours later, for theability to remember the electric shock.

If scolopamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment.

    ______________________________________                                                                   % of Animals                                                      Dose        With Scopolamine                                                  mg/kg by    Induced Memory                                     Compound       Body Weight Deficit Reversed                                   ______________________________________                                        N-(1H-Pyrrol-1-yl)-                                                                          0.63        21                                                 4-pyridinamine                                                                N-Methyl-N-(1H-                                                                              2.5         43                                                 pyrrol-1-yl)-4-                                                               pyridinamine                                                                  1-[N-Methyl-N-(4-                                                                            1.25        60                                                 pyridinyl)]amino-                                                             pyrrol-2-                                                                     carboxaldehyde                                                                N-[2-(1-hydroxyethyl)-                                                                       5.0         19                                                 1H-pyrrol-1-yl]-N-                                                            methyl-4-pyridinamine                                                         N-(2-Chloro-1H-pyrrol-                                                                       2.5         33                                                 1-yl)-N-ethyl-4-                                                              pyridinamine                                                                  Pilocarpine    5           23                                                 (reference compound)                                                          ______________________________________                                    

Additionally, some of the compounds of this invention exhibitantidepressant activities, which activities being particularly helpfulfor patients suffering from Alzheimer's disease. Further, the compoundsof this invention are in general less toxic than heretofore knowncompounds such as tacrine and physostigmine, making them moretherapeutically acceptable.

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; and excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% and about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that a parenteraldosage unit contains between 0.5 to 100 milligrams of active compound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

Examples of the compounds of this invention include:

N-(1H-Pyrrol-1-yl)-4-pyridinamine;

N-methyl-N-(1H-pyrrol-1-yl)-3-nitro-4-pyridinamine;

3-Nitro-N-(1H-pyrrol-1-yl)-4-pyridinamine;

N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)-N'-methylurea;

N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)carbamic acid ethyl ester;

N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)propanamide;

N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)linoleamide;

3,4-Dimethoxy-N-(4-pyridinyl)-N-(1H-pyrrol-1-yl)phenyl acetamide;

N-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridinyl)-3,4-dimethoxyphenylacetamide;

N-Methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine;

N-Ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine;

N-(2-Chloro-1H-pyrrol-1-yl)-N-methyl-4-pyridinamine;

N-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridinyl)carbamic acid ethyl ester;

N-(2-Chloro-1H-pyrrol-1-yl)-N-ethyl-4-pyridinamine;

1-[N-Methyl-N-(3-nitro-4-pyridinyl)amino]pyrrol-3-carboxaldehyde;

1-[N-Methyl-N-(4-pyridinyl)]aminopyrrol-3-carboxaldehyde;

1-[N-Methyl-N-(4-pyridinyl)]aminopyrrol-2-carboxaldehyde;

α-methyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol;

N-(2-Chloro-1H-pyrrol-1-yl)-4-pyridinamine;

4-[N-(1H-Pyrrol-1-yl)amino]-3-pyridinamine;

4-[N-Methyl-N-(1H-pyrrol-1-yl)amino]-3-pyridinamine;

N-[3-[4-[[N-Methyl-N-(1H-pyrrol-1-yl)]amino]]pyridinyl]-formamide;

2-(n-Butyl)-N-methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine;

N-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridyl)-linoleamide;

N-Propyl-N-(1H-pyrrol-1-yl)-4-pyridinamine;

α-Ethyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol;

α-Propyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol;

N-(4-Nitrophenyl)-N-(1H-pyrrol-1-yl)-4-pyridinamine;

N-Phenylmethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine;

1-[N-Ethyl-N-(4-pyridinyl)]aminopyrrol-2-carboxaldehyde;

1-[N-Ethyl-N-(4-pyridinyl)]aminopyrrol-3-carboxaldehyde;

1-[[N-Methyl-N-(4-pyridinyl)amino]-1H-pyrrole-2-methanol;

N-(2-Methoxymethyl-1H-pyrrol-1-yl)-N-methyl-4-pyridinamine; and

N-(2-Formyl-1H-pyrrol-1-yl)-N-(2,3,5,6-tetrachloro-4-pyridinyl) carbamicacid ethyl ester.

EXAMPLE 1 N-(1H-Pyrrol-1-yl)-4-pyridinamine

A solution of 4-chloropyridine (15 g) and N-aminopyrrole (18 g) in 225ml of diglyme was stirred at 150° C. for one hour and thereafter cooled,diluted with water and basified with sodium carbonate. The mixture wasextracted with ethyl acetate, and the organic extract was dried overanhydrous magnesium sulfate, filtered and evaporated to an oil. This oilwas purified by high performance liquid chromatography (HPLC hereafter)using silica gel and ethyl acetate to give 12 g of a solid, mp 150° C.Five grams of the solid was recrystallized twice from benzene to give2.8 g of crystals, mp 153°-154° C.

Analysis Calculated for C₉ H₉ N_(3:) 67.90% C, 5.70% H, 26.40% N, Found:67.53% C, 5.81% H, 26.18% N.

EXAMPLE 2 N-methyl-N-(1H-pyrrol-l-yl)-3-nitro-4-pyridinaminehydrochloride

A solution of N-methylaminopyrrole (8.8 g) and 4-chloro-3-nitropyridine(14.5 g) in 200 ml of dimethylformamide was stirred at ambienttemperature for 17 hours.

The reaction mixture was then added to an aqueous sodium bicarbonatesolution and extracted with diethyl ether (2×). The combined organicswere washed with water (3×) and dried (saturated sodium chloridesolution, anhydrous magnesium sulfate). This was concentrated to 19.4 gof a solid. This was triturated with hexane to give 15.6 g of solid, mp91°-99° C.

A 5.0 g portion of this material was converted into its hydrochloridesalt via ethereal hydrochloric acid to give 5.6 g of a solid, m.p.:begins darkening @165° C., 234°-238° C. This was twice recrystallizedfrom isopropanol:methanol (3:1) to give 3.4 g of a solid, m.p.: beginsdarkening @210° C., 235°-236° C., decomp.

Analysis Calculated for C₁₉ H₁₀ N₄ O₂.HCL: 47.16% C, 4.35% H, 22.00% N,Found: 47.07% C, 4.19% H, 22.09% N.

EXAMPLE 3 3-Nitro-N-(1H-pyrrol-1-yl)-4-pyridinamine hydrochloride

A solution of 2,5-dimethoxytetrahydrofuran (5.8 g) in 100 ml of glacialacetic acid was heated to 110° C. in an oil bath. To this was slowlyadded a solution of 4-hydrazino-3-nitropyridine (5.6 g in 300 ml ofglacial acetic acid). The solution was heated an additional 0.5 hr.

The mixture was then concentrated to a solid and taken up in aqueous Na₂CO₃. This was extracted with ethyl ether (3×). The organics were thenwashed with water (1×) and dried (saturated sodium chloride solution,anhydrous sodium sulfate). This was then concentrated to a solid.

The pyrrole was purified via flash chromatography (ether/hexane) toyield 3.1 g of a solid, m.p. 138°-143° C. This was converted to thehydrochloride salt in ethyl ether to give 3.1 g of a solid, m.p.228°-232° C. d. This was recrystallized from isopropanol:methanol (5:1)to give 2.2 g of a solid, m.p. 235°-238° C., decomp.

Analysis Calculated for C₉ H₈ N₄ O₂.HCl: 44.92% C, 3.77% H, 23.28% N,Found: 44.54% C, 3.73% H, 23.06% N.

EXAMPLE 4 N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)-N'-methylurea

A solution containing 4 g of N-(1H-pyrrol-1-yl)-4-pyridinamine 1.6 g ofmethyl isocyanate in 125 ml of benzene was stirred at 50° C. for twohours, and thereafter cooled and evaporated to 6 g of a solid. Thismaterial was purified by HPLC (silica gel, 50% ethyl acetate indichloromethane) to give 5 g of a solid, mp 156°-160° C. This materialwas recrystallized twice from benzene to give 2.6 g of crystals, mp162°-163° C.

Analysis Calculated for C₁₁ H₁₂ N₄ O: 61.09% C, 5.59% H, 25.91% N,Found: 61.19% C, 5.67% H, 25.89% N.

EXAMPLE 5 N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)carbamic acid ethyl ester

To a solution containing 9 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 15g of sodium bicarbonate in 350 ml of dichloromethane was added asolution containing 6.7 g of ethyl chloroformate in 50 ml ofdichloromethane.

After stirring twenty hours at ambient temperature, the reaction mixturewas washed with water and saturated sodium chloride and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 12 g of anoil. This oil was purified by HPLC (silica gel, 20% ethyl acetate indichloromethane) to give 10 g of a solid. This material wasrecrystallized from petroleum ether to give long needles, mp 54°-56° C.

Analysis Calculated for C₁₂ H₁₃ N₃ O₂ : 62.32% C, 5.67% H, 18.17% N,Found: 62.07% C, 5.56% H, 18.32% N.

EXAMPLE 6 N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)propanamide

To a solution containing 2.9 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and5 g of sodium bicarbonate in 100 ml of dichloromethane was added asolution containing 1.9 g of propionyl chloride in 20 ml ofdichloromethane.

After stirring twenty hours at ambient temperature, the reaction mixturewas washed with water and saturated sodium chloride and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 4.5 g of asolid. This material was purified by HPLC (silica gel, 15% ethyl acetatein dichloromethane) to give 3.3 g of a solid. This material wasdistilled via a Kugelrohr apparatus to give 2.9 g of crystals, mp80°-82° C., bp 130°-135° C. Ε 0.1 mm Hg.

Analysis Calculated for C₁₂ H₁₃ N₃ O: 66.95% C, 6.09% H, 19.53% N,Found: 66.98% C, 6.33% H, 19.49% N.

EXAMPLE 7 N-(4-Pyridinyl)-N-(1H-pyrrol-1-yl)linoleamide

A solution of linoleic acid (7 g) and thionyl chloride (5 g) in 25 ml ofbenzene was stirred at 80° for four hours, and thereafter cooled andevaporated to 8 g of an oil. To a solution of linoleic acid chloride in200 ml of dichloromethane containing sodium bicarbonate (7 g) was addedN-(1H-pyrrol-1-yl)-4-pyridinamine (4 g). After stirring twenty hours atambient temperature the reaction mixture was washed with water andsaturated sodium chloride and thereafter dried over magnesium sulfate,filtered and evaporated to 11 g of an oil. This oil was purified by HPLC(silica gel, 7% ethyl acetate in dichloromethane) to give 8.3 g of anoil. This oil was purified by column chromatography (alumina, ether) togive 5.1 g of an oil.

Analysis Calculated for C₂₇ H₃₉ N₃ O: 76.91% C, 9.32% H, 9.97% N, Found:76.78% C, 9.41% H, 9.75% N.

EXAMPLE 83,4-Dimethoxy-N-(4-pyridinyl)-N-(1H-pyrrol-1-yl)phenylacetamidehydrochloride

To a suspension of (3,4-dimethoxyphenyl)acetic acid (10 g) in 75 ml ofbenzene was added thionyl chloride (12 g). The resultant solution wasstirred at 80° for three hours, and thereafter cooled and evaporated to10.5 g of an oil.

To a solution of the acid chloride (5 g) in 150 ml of dichloromethanecontaining sodium bicarbonate (5 g) was addedN-(1H-pyrrol-1-yl)-4-pyridinamine (3 g). After stirring twenty hours atambient temperature the reaction mixture was washed with water andsaturated sodium chloride and thereafter dried over anhydrous magnesiumsulfate, filtered and evaporated to 6.5 g of an oil. This oil waspurified by HPLC (silica, 20% ethyl acetate in dichloromethane) to give4.1 g of the desired product as a solid, mp 98°-99° C. This material wasdissolved in 25 ml of warm isopropanol, filtered and acidified by theaddition of ethereal hydrochloric acid. The crystals which formed uponcooling were collected and dried to give 4.2 g of crystals, mp 212°-213°C.

Analysis Calculated for C₁₉ H₁₉ N₃ O₃.HCl: 61.04% C, 5.39% H, 11.24% N,Found: 61.03% C, 5.61% H, 11.00% N.

EXAMPLE 9N-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridinyl)-3,4-dimethoxyphenylacetamidehydrochloride

A solution of (3,4-dimethoxyphenyl)acetic acid (3 g) and thionylchloride (4 g) in 25 ml of benzene was stirred one hour at reflux andthereafter cooled and evaporated to an oil. To a solution of the acidchloride (3.5 g) in 50 ml of dichloromethane was added sodiumbicarbonate (5 g) and N-(2-chloro-1H-pyrrol-1-yl)]-4-pyridinamine (2.3g). After stirring three hours at ambient temperature, the reactionmixture was evaporated, stirred with 300 ml of water and extracted withether. The organic extract was washed with water and saturated sodiumchloride and thereafter dried over anhydrous magnesium sulfate, filteredand evaporated to 4 g of an oil. This oil was purified by HPLC (silica,20% ethyl acetate in dichloromethane) to give 3.4 g of an oil. This oilwas dissolved in 25 ml of warm isopropanol, and filtered and thereafterconverted to the hydrochloride salt by the addition of etherealhydrochloric acid. The crystals which formed upon cooling and dilutionwith ether were collected and dried to give 3.3 g of a solid, mp153°-154° C.

Analysis Calculated for C₁₉ H₁₈ ClN₃ O₃.HCl: 55.89% C, 4.69% H, 10.29%N, Found: 55.63% C, 4.69% H, 10.36% N.

EXAMPLE 10 N-Methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine hydrochloride

To an ice-cooled suspension containing 1.5 g of sodium hydride in 5 mlof dimethylformamide was slowly dropped a solution ofN-(1H-pyrrol-1-yl)-4-pyridinamine (4 g) in 10 ml of dimethylformamide.After the initial brisk hydrogen evolution subsided, the reactionmixture was slowly warmed to ambient temperature and thereafter warmedat 50° C. for thirty minutes. The reaction mixture was again cooled withan ice bath and a solution of dimethyl sulfate (3.8 g) in 5 ml ofdimethylformamide was slowly added.

After thirty minutes, the reaction mixture was stirred with 300 ml ofice water and extracted with dichloromethane. The organic extract waswashed with water and saturated sodium chloride and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 4 g of anoil. This oil was purified by HPLC (silica gel, ethyl acetate) to give3.5 g of an oil. This oil was dissolved in 10 ml of warm isopropanol andfiltered, and thereafter converted to the hydrochloride salt by theaddition of ethereal hydrochloric acid. The crystals which formed uponcooling were collected and dried to give 3.1 g of crystals, mp 226°-227°C. These crystals were sublimed at 135°-150° C. @0.01 mm Hg to give 2.9g of crystals, mp 226°-227° C.

Analysis Calculated for C₁₀ H₁₁ N₃.HCl: 57.28% C, 5.77% H, 20.04% N,Found: 57.39% C, 5.78% H, 19.99% N.

EXAMPLE 11 N-Ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine hydrochloride

A solution of N-(1H-pyrrol-1-yl)-4-pyridinamine (4 g) in 20 ml ofdimethylformamide was slowly added dropwise to an ice-cooled suspensioncontaining 1.2 g of sodium hydride in 5 ml of dimethylformamide. Afterthe initial brisk reaction subsided, the mixture was stirred cold forthirty minutes, and thereafter a solution of diethyl sulfate (4.3 g) in10 ml of dimethylformamide was added. After stirring twenty hours atambient temperature, the reaction mixture was quenched with 500 ml ofwater and extracted with dichloromethane. The organic extract was washedwith water and saturated sodium chloride and thereafter dried overanhydrous magnesium sulfate, filtered and evaporated to 4.3 g of an oil.This oil was purified by HPLC (silica, ethyl acetate) to give 3.7 g ofan oil. This oil was dissolved in 10 ml of warm isopropanol, filtered,and acidified by the addition of ethereal HCl. The product which formedupon cooling was collected and dried to give 3.3 g of a solid, mp224°-225° C.

Analysis Calculated for C₁₁ H₁₃ N₃.HCl: 59.06% C, 6.31% H, 18.79% N,Found: 58.84% C, 6.52% H, 18.61% N,

EXAMPLE 12 N-(2-Chloro-1H-pyrrol-1-yl)-N-methyl]-4-pyridinaminehydrochloride

To a solution of N-Methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (7.7 g) in300 ml of anhydrous tetrahydrofuran cooled to 5° with an ice bath wasadded N-chlorosuccinimide (5.2 g). The reaction mixture was stirredsixty hours at ambient temperature, and thereafter additional NCS (0.9g) was added. After stirring an additional sixteen hours at ambienttemperature, the reaction mixture was stirred with an aqueous solutionof sodium bisulfite and extracted with ether. The organic extract waswashed with water and saturated sodium chloride and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 9.5 g of anoil. This oil was purified by HPLC (silica, ethyl acetate) to give 4.4 gof an oil. This oil was purified by column chromatography (alumina,ether) to give 2.4 g of the desired product as an oil. This oil wasdissolved in 25 ml of isopropanol, filtered, and converted to thehydrochloride salt by the addition of ethereal hydrochloric acid. Thesolution was diluted with 25 ml of ether and cooled. The resultantprecipitate was collected and dried to give 2.5 g of crystals, mp230°-231° C.

Analysis Calculated for C₁₀ H₁₀ ClN₃.HCl: 49.20% C, 4.54% H, 17.22% N,Found: 49.15% C, 4.67% H, 17.34% N.

EXAMPLE 13 N-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridinyl)carbamic acidethyl ester hydrochloride

To a solution of N-(4-pyridinyl)-N-(1H-pyrrol-1-yl) carbamic acid ethylester (9 g) in 100 ml of anhydrous tetrahydrofuran warmed to 50° wasslowly dropped a solution of N-chlorosuccinimide (5.2 g) in 75 ml ofanhydrous tetrahydrofuran. After stirring seven hours at 50°, thereaction mixture was cooled, stirred with an aqueous solution of sodiumbisulfite and extracted with ethyl acetate. The organic extract waswashed with water and saturated sodium chloride and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 11.5 g ofan oil. This oil was purified by HPLC (silica, 20% ethyl acetate indichloromethane) to give 3.8 g of the desired product as a solid. Thismaterial was converted to the hydrochloride salt and twicerecrystallized from isopropanol-ether to give 3.3 g of crystals, d139°-140° C.

Analysis Calculated for C₁₂ H₁₂ ClN₃ O₂.HCl: 47.70% C, 4.34% H, 13.91%N, Found: 47.58% C, 4.36% H, 13.97% N.

EXAMPLE 14 N-(2-Chloro-1H-pyrrol-1-yl)-N-ethyl-4-pyridinaminehydrochloride

To a solution of N-ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (10.2 g) in200 ml of anhydrous tetrahydrofuran was added N-chlorosuccinimide (7.3g). After stirring twenty hours at ambient temperature, the reactionmixture was stirred with an aqueous solution of sodium sulfite andextracted with dichloromethane. The organic extract was washed withwater and saturated sodium chloride and thereafter dried over anhydrousmagnesium sulfate, filtered and evaporated to 12 g of an oil. This oilwas purified by HPLC (silica, 25% dichloromethane in ethyl acetate) togive 3.7 g of the desired product as an oil. This oil was converted tothe hydrochloride salt and twice recrystallized from isopropanol-etherto give 3 1 g of crystals, mp 206°-207° C.

Analysis Calculated for C₁₁ H₁₂ CIN₃.HCl: 51.18% C, 5.08% H, 16.28% N,Found: 51.43% C, 4.95% H, 16.36% N.

EXAMPLE 151-[N-Methyl-N-(3-nitro-4-pyridinyl)]aminopyrrol-3-carboxaldehyde

To chilled dimethylformamide (5.5 ml) was slowly added POCl₃ (7.5 ml).This was stirred for 10 minutes at ambient temperature and diluted with10 ml of 1,2-dichloroethane.

To this was added a solution ofN-methyl-N-(1H-pyrrol-1-yl)-3-nitro-4-pyridinamine (12.0 g) in 125 ml of1,2-dichloroethane. This was heated at 80° C. for 4.5 hours.

The reaction was quenched with 45 g of sodium acetate trihydratedissolved to a total volume of 125 ml with water. This was refluxed for1 hour, cooled and diluted with dichloromethane. The layers wereseparated and the aqueous phase was extracted with dichloromethane (2×).The combined organics were then washed with a saturated Na₂ CO₃ solutionand dried (saturated sodium chloride solution, anhydrous magnesiumsulfate). This was concentrated to a semi-solid.

The aldehyde was purified via HPLC (10% ethyl acetate/dichloromethane)to yield 7.3 g of the 2-isomer and 2.35 g of the 3-isomer, mp 128°-142°C. The 3-isomer was recrystallized from isopropyl ether:methanol (5:1)to give 1.0 g of a solid, mp 145°-148° C.

Analysis Calculated for C₁₁ H₁₀ N₄ O₃ : 53.66% C, 4.09% H, 22.75% N,Found: 53.23% C, 4.09% H, 22.73% N.

EXAMPLE 16 1-[N-Methyl-N-(4-pyridinyl)]aminopyrrol-3-carboxaldehydemaleate

To cold dimethylformamide (7 g) was slowly added phosphorous oxychloride(14.7 g). The resultant clear complex was stirred one hour at ambienttemperature and thereafter dissolved in 25 ml of dichloroethane. To thiscooled solution was slowly added a solution ofN-methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (15 g) in 25 ml ofdichloroethane. After stirring twelve hours at 95°, the reaction mixturewas cooled, and a solution of sodium acetate trihydrate (60 g) in 200 mlof water was slowly added. The resultant mixture was stirred one hour at95° and thereafter cooled, stirred with 500 ml of water and basifiedwith sodium carbonate. The oil which separated was extracted withdichloromethane, washed with water and saturated sodium chloride andthereafter dried over anhydrous magnesium sulfate, filtered andevaporated to 18 g of an oil. This oil was purified by HPLC (silica,ethyl acetate) to give 10.2 g of the pyrrol-2-aldehyde as a solid, mp71°-74° C. Further elution yielded 2 g of the pyrrol-3-aldehyde as anoil. This oil was converted to the maleate salt and recrystallized fromisopropanol to give 1.9 g of crystals, mp 139°-140° C.

Analysis Calculated for C₁₁ H₁₁ N₃ O.C₄ H₄ O₄ : 56.78% C, 4.77% H,13.25% N, Found: 56.64% C, 4.87% H, 13.20% N.

EXAMPLE 17 1-[N-Methyl-N-(4-pyridinyl)]aminopyrrol-2-carboxaldehydemaleate

To cold dimethylformamide (7 g) was slowly added phosphorous oxychloride(14.7 g). The resultant clear complex was stirred one hour at ambienttemperature and thereafter dissolved in 25 ml of dichloroethane. To thiscooled solution was slowly added a solution ofN-methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (15 g) in 25 ml ofdichloroethane. After stirring twelve hours at 95°, the reaction mixturewas cooled, and a solution of sodium acetate trihydrate (60 g) in 200 mlof water was slowly added. The resultant mixture was stirred one hour at95°, and thereafter cooled, stirred with 500 ml of water and basifiedwith sodium carbonate. The oil which separated was extracted withdichloromethane, washed with water and saturated sodium chloride andthereafter dried over anhydrous magnesium sulfate, filtered andevaporated to 18 g of an oil. This oil was purified by HPLC (silica,ethyl acetate) to give 10.2 g of the pyrrol-2-aldehyde as a solid, mp71°-74° C. A 2.5 g portion of this solid was converted to the maleatesalt and recrystallized from isopropanol to give 3.4 g of crystals, m.p.118°-119° C.

Analysis Calculated for C₁₁ H₁₁ N₃ O.C₄ H₄ O₄ : 56.78% C, 4.77% H,13.25% N, Found: 56.79% C, 4.83% H, 13.22% N.

EXAMPLE 18α-methyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanolmaleate

To a cooled solution of1-[N-methyl-N-(4-pyridinyl)]-aminopyrrol-2-carboxaldehyde (3 g) in 50 mlof anhydrous tetrahydrofuran was slowly dropped methylmagnesium bromide(3.2M in ether, 5.1 ml). After stirring two hours at ambienttemperature, the reaction mixture was stirred with 300 ml of saturatedammonium chloride and extracted with ethyl acetate. The organic extractwas washed with water and saturated sodium chloride and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 3.4 g of anoil. This oil was purified by HPLC (silica, 5% methanol indichloromethane) to give 3.0 g of an oil. This oil was converted to themaleate salt and recrystallized from isopropanol-ether to give 3.6 g ofcrystals, mp 118°-119° C.

Analysis Calculated for C₁₂ H₁₅ N₃ O.C₄ H₄ O₄ : 57.65% C, 5.75% H,12.61% N, Found: 57.66% C, 5.87% H, 12.39% N.

EXAMPLE 19 N-(2-Chloro-1H-pyrrol-1-yl)-4-pyridinamine hydrochloride

A mixture prepared from a solution ofN-(2-chloro-1H-pyrrol-1-yl)-N-(4-pyridinly)carbamic acid ethyl ester (6g) in 50 ml of ethanol and 20 ml of 10% aqueous sodium hydroxidesolution was warmed for 15 minutes on a steam bath, and thereaftercooled, diluted with 500 ml of water and extracted with dichloromethane.The organic extract was washed with water and saturated sodium chlorideand thereafter dried over anhydrous magnesium sulfate, filtered andevaporated to 5 g of an oil. This oil was purified by HPLC (silica,ethyl acetate) to give 3.5 g of a solid, mp 115°-118° C. This materialwas converted to the hydrochloride salt and recrystallized twice fromisopropanol-ether to give 3.4 g of crystals, mp 172°-173° C.

Analysis Calculated for C₉ H₈ ClN₃.HCl: 46.98% C, 3.94% H, 18.27% N,Found: 46.76% C, 3.80% H, 18.13% N.

EXAMPLE 20 4-[N-(1H-Pyrrol-1-yl)amino]-3-pyridinamine hydrochloride

In a Parr shaker apparatus was placed a mixture prepared from 6.0 g of3-nitro-N-(1H-pyrrol-1-yl)-4-pyridinamine, 280 mg of 10% palladium oncarbon, 50 ml of ethyl acetate and 150 ml of isopropanol. This waspressurized to 50 psi (pounds per square inch) with hydrogen and shakenfor 8 hours at ambient temperature. The catalyst was then filtered andthe solution was concentrated to an oil.

The amine was purified via HPLC (8% methanol/dichloromethane) to yield3.4 g of an oil. This was converted to the hydrochloric acid salt indiethyl ether to yield 25 g of a solid, mp 200°-210° C. d. This wasrecrystallized from isopropanol/diethyl ether to give 2.25 g of a solid,mp 207°-209° C. decomp.

Analysis Calculated for C₉ H₁₀ N₄.HCl: 51.31% C, 5.26% H, 26.59% N,Found: 51.51% C, 5.42% H, 26.29% N.

EXAMPLE 21 4-[[N-Methyl-N-(1H-pyrrol-1-yl)amino]]-3-pyridinamine

In a Parr shaker apparatus was placed a mixture prepared from 5.0 g ofN-methyl-N-(1H-pyrrol-1-yl)-3-nitro-4-pyridinamine, 310 mg of 10%palladium on carbon, 175 ml of isopropanol and 30 ml of methanol. Thiswas shaken for 18 hours at ambient temperature.

The catalyst was filtered and the solution was concentrated to give 4.3g of a solid, mp 100°-106° C. A 2.6 portion of this material wassublimed under high vacuum at an oil bath temperature of 109° C. to give2.1 g of crystals, mp 108°-111° C.

Analysis Calculated for C₁₀ H₁₂ N₄ : 63.81% C, 6.43% H, 29.77% N, Found:63.67% C, 6.34% H, 29.80% N.

EXAMPLE 22N-[3-[4-[[N-Methyl-N-(1H-pyrrol-1-yl)]amino]]-pyridinyl]-formamide

A solution of 4-[[N-methyl-N-(1H-pyrrol-1-yl)]amino]-3-pyridinamine (6.9g) in 25 ml of phenyl formate was stirred at ambient temperature for 40hours.

The reaction mixture was added to 10% aqueous hydrochloric acid solutionand this was washed with diethyl ether (2×). The aqueous phase wasbasified with aqueous sodium hydroxide and extracted with ethyl acetate(3×). The combined organics were dried (saturated sodium chloridesolution, anhydrous magnesium sulfate) and concentrated to an oil.

The amide was purified via flash chromatography (4%methanol/dichloromethane) to yield 5.3 g of a solid, m.p. 119°-125° C. Aportion of this solid was recrystallized from isopropyl ether:methanol(10:1) to give an analytically pure solid, m.p. 122°-125° C.

Analysis Calculated for C₁₁ H₁₂ N₄ O: 61.10% C, 5.59% H, 25.91% N,Found: 60.88% C, 5.59% H, 26.21% N.

EXAMPLE 23 2-(n-Butyl)-N-methyl-N-(1H-pyrrol-1-yl-4-pyridinamine maleate

To a solution of N-methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (4.2 g) in50 ml of anhydrous tetrahydrofuran cooled to -78° under nitrogen, wasslowly dropped n-butyllithium (2.1M in hexane, 13.8 ml). After theaddition, the mixture was slowly warmed to ambient temperature andcooled again to 5°, and 30 ml of tetrahydrofuran was added. Afterstirring thirty minutes at ambient temperature, the reaction mixture wasstirred with 300 ml of water and extracted with ethyl acetate. Theorganic extract was washed with water and saturated sodium chloride,dried over anhydrous magnesium sulfate, filtered and evaporated to 8.2 gof an oil. This oil was purified by HPLC (silica, 50% ethylacetate-dichloromethane) to give 3.7 g of an oil. This oil was dissolvedin 25 ml of warm isopropanol, and filtered, and a solution of maleicacid (1.9 g) in isopropanol was added. The crystals which formed uponcooling were collected and dried to give 5 g of crystals, mp 98°-100° C.

Analysis Calculated for C₁₄ H₁₉ N₃.C₄ H₄ O₄ : 62.59% C, 6.71% H, 12.17%N, Found: 62.22% C, 6.81% H, 11.90% N.

EXAMPLE 24 N-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridyl)-linoleamide2-naphthalene sulfonate

A solution of linoleic acid (10 g) and thionyl chloride (6.4 g) in 75 mlof benzene was stirred for two hours at 85°, and thereafter cooled andevaporated to 12 g of an oil. To a solution of the acid chloride in 100ml of dichloromethane was added sodium bicarbonate (5 g) and then4-[N-(2-chloro-1H-pyrrol-1-yl)]aminopyridine (3.8 g). After stirringovernight at ambient temperature the reaction mixture was washed withwater and saturated sodium chloride solution and thereafter dried overanhydrous magnesium sulfate, filtered and evaporated to 14 g of an oil.This oil was purified by high-pressure liquid chromatography (silica, 4%ethyl acetate in dichloromethane) to give 6.6 g of an oil. This oil waspurified by column chromatography (alumina, ether) to give 5.9 g of anoil. A 2.3 g portion of the oil was converted to the 2-naphthalenesulfonate in ether, collected and dried to give 2.7 g of a solid, mp127°- 128° C.

Analysis Calculated for C₂₇ H₃₈ ClN₃ O.C₁₀ H₈ SO₃ : 66.89% C, 6.98% H,6.33% N, Found: 67.08% C, 7.02% H, 6.34% N.

EXAMPLE 25 N-Propyl-N-(1H-pyrrol-1-yl)-4-pyridinamine hydrochloride

A solution of N-(1H-pyrrol-1-yl)-4-pyridinamine (3 g) in 25 ml ofdimethylformamide was slowly dropped into a suspension containing 1 g ofsodium hydride in 5 ml of dimethylformamide. After the anion formation,the reaction mixture was cooled with an ice bath and a solution of1-bromopropane (2.8 g) in 5 ml of dimethylformamide was slowly added.After stirring one hour, the reaction mixture was quenched with waterand extracted with dichloromethane. The organic extract was washed withwater and saturated sodium chloride solution, and thereafter dried overanhydrous magnesium sulfate, filtered and evaporated to an oil. This oilwas purified by flash chromatography (silica, ethyl acetate) to give 5 gof an oil. This oil was converted to the hydrochloride salt in warmisopropanol. The crystals which formed upon dilution with ether werecollected and dried to give 3.3 g of a solid, d 230°-232° C. Thismaterial was recrystallized from isopropanol-ether to give 2.6 g ofcrystals, d 232°-233° C.

Analysis Calculated for C₁₂ H₁₅ N₃.HCl: 60.62% C, 6.78% H, 17.68% N,Found: 60.70% C, 6.88% H, 17.67% N.

EXAMPLE 26α-Ethyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol

To a cooled solution of1-[N-methyl-N-(4-pyridinyl)]-aminopyrrol-2-carboxaldehyde (3.5 g) in 75ml of tetrahydrofuran was slowly dropped a solution of ethylmagnesiumbromide (2M in tetrahydrofuran, 10.5 ml). After thirty minutes thereaction mixture was stirred with 200 ml of saturated ammonium chloridesolution, basified with sodium carbonate and extracted with ethylacetate. The organic extract was washed with water and saturated sodiumchloride solution and thereafter dried over anhydrous magnesium sulfate,filtered and evaporated to 4 g of an oil. This oil was crystallized fromisopropyl ether to give 3 g of a solid, m.p. 86°-8820 C.

Analysis Calculated for C₁₃ H₁₇ N₃ O: 67.50% C, 7.41% H, 18.17% N,Found: 67.23% C, 7.39% H, 18.06% N.

EXAMPLE 27α-Propyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol

To a cooled solution of1-[N-methyl-N-(4-pyridinyl)]-aminopyrrol-2-carboxaldehyde (3.5 g) in 75ml of tetrahydrofuran was slowly dropped a solution of propylmagnesiumchloride (2M in ether, 10.5 ml). After thirty minutes the reactionmixture was stirred with saturated ammonium chloride solution, basifiedwith sodium carbonate and extracted with ethyl acetate. The organicextract was washed with water and saturated sodium chloride solution andthereafter dried over anhydrous magnesium sulfate, filtered andevaporated to 4.5 g of an oil. This oil was crystallized from isopropylether to give 3.2 g of crystals, mp 98°-99° C.

Analysis Calculated for C₁₄ H₁₉ N₃ O: 68.54% C, 7.81% H, 17.13% N,Found: 68.49% C, 7.76% H, 17.23% N.

EXAMPLE 28 N-(4-Nitrophenyl)-N-(1H-pyrrol-1-yl)-4-pyridinaminehydrochloride

A solution of N-(1H-pyrrol-1-yl)-4-pyridinamine (4 g) in 25 ml ofdimethylformamide was slowly added to an ice-cooled stirred suspensioncontaining 1.2 g of sodium hydride in 10 ml of dimethylformamide. Afterthe anion formation, a solution of 1-fluoro-4-nitrobenzene (4.2 g) in 10ml of dimethylformamide was slowly added. After thirty minutes, thereaction mixture was stirred with ice water and extracted with ethylacetate. The organic extract was washed with water and saturated sodiumchloride solution and thereafter dried over anhydrous magnesium sulfate,filtered and evaporated to 10 g of an oil. This material was purified byflash chromatography (silica, 10% ethyl acetate in dichloromethane) togive 5.5 g of a solid, mp 98°-99° C.

This material was converted to the hydrochloride salt in isopropanol togive 5.4 g of crystals, d 269°-270° C.

Analysis Calculated for C₁₅ H₁₂ N₄ O₂.HCl: 56.88% C, 4.14% H, 17.69% N,Found: 57.09% C, 4.35% H, 17.69% N.

EXAMPLE 29 N-Phenylmethyl-N-(1H-pyrrol-1-yl)-4-pyridinaminehydrochloride

A solution of N-(1H-pyrrol-1-yl)-4-pyridinamine (4 g) in 20 ml ofdimethylformamide was slowly added to an ice-cooled stirred suspensioncontaining 1.1 g of sodium hydride in 5 ml of dimethylformamide. Afterthe anion formation, a solution of benzylbromide (4.7 g) in 10 ml ofdimethyformamide was slowly added. After stirring thirty minutes, thereaction mixture was stirred with 500 ml of ice water and extracted withether. The organic extract was washed with water and saturated sodiumchloride solution thereafter and dried over anhydrous magnesium sulfate,filtered and evaporated to 6 g of an oil. This material was purified byflash chromatography (silica, ethyl acetate) to give 4.4 g of theproduct as a solid, mp 77°-79° C. This material was converted to thehydrochloride salt in 20 ml of warm ethanol by the addition of etherealHCl. The crystals which formed upon cooling and dilution with ether werecollected and dried to give 3.1 g of white crystals, mp 210°-211° C.

Analysis Calculated for C₁₆ H₁₅ N₃.HCl: 67.24% C, 5.64% H, 14.71% N,Found: 67:15% C, 5.675H, 14.76% N.

EXAMPLE 30 1-[N-Ethyl-N-(4-pyridinyl)]aminopyrrol-2-carboxaldehydehydrochloride

To cold dimethylformamide (11.1 g) was slowly added phosphorousoxychloride (23.2 g). The resultant clear complex was stirred one hourat ambient temperature and thereafter a solution ofN-ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (20.5 g) in 135 ml ofdichloroethane was added. After stirring twelve hours at 95° thereaction mixture was cooled and hydrolyzed for one hour at 95° with asolution of sodium acetate trihydrate (40 g) in 150 ml of water. Thereaction mixture was cooled, basified with sodium carbonate andextracted with dichloromethane. The organic extract was washed withwater and saturated sodium chloride solution and thereafter dried overanhydrous magnesium sulfate, filtered and evaporated to 24 g of an oil.This oil was purified first by flash chromatography (silica,dichloromethane, then 10% ethyl acetate in dichloromethane), then byhigh-pressure liquid chromatography (silica, ethyl acetate) to give 8 gof the pyrrol-2-aldehyde as an oil and 8 g of the pyrrol-3-aldehyde asan oil. 2.5 g of the pyrrol-2-aldehyde was converted to thehydrochloride salt in 2-propanol to give 2.2 g of crystals, mp 214°-215°C.

Analysis Calculated for C₁₂ H₁₃ N₃ O.HCl: 57.26% C, 5.61% H, 16.70% N,Found: 57.25% C, 5.76% H, 16.84% N.

EXAMPLE 31 1-[N-Ethyl-N-(4-pyridinyl)]aminopyrrol-3-carboxaldehydemaleate

To cold dimethylformamide (11.1 g) was slowly added phosphorousoxychloride (23.2 g). The resultant clear complex was stirred one hourat ambient temperature and thereafter a solution ofN-ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (20.5 g) in 135 ml ofdichloroethane was added. After stirring twelve hours at 95° thereaction mixture was cooled and hydrolyzed for one hour at 95° with asolution of sodium acetate trihydrate (40 g) in 150 ml of water. Thereaction mixture was cooled, basified with sodium carbonate andextracted with dichloromethane. The organic extract was washed withwater and saturated sodium chloride solution and thereafter dried overanhydrous magnesium sulfate, filtered and evaporated to 24 g of an oil.This oil was purified first by flash chromatography (silica,dichloromethane, then 10% ethyl acetate in dichloromethane), then byhigh-pressure liquid chromatography (silica, ethyl acetate) to give 8 gof the pyrrol-2-aldehyde as an oil and 8 g of the pyrrol-3-aldehyde asan oil. 2.5 g of the pyrrol-3-aldehyde was converted to the maleate saltin 2-propanol to give 3.4 g of crystals, d 135°-136° C.

Analysis Calculated for C₁₂ H₁₃ N₃ O.C₄ H₄ O₄ : 58.00% C, 5.17% H,12.69% N, Found: 58.04% C, 5.12% H, 12.67% N.

EXAMPLE 32 1-[[N-Methyl-N-(4-pyridinyl)amino]-1H-pyrrole-2-methanol

To a solution of1-[N-methyl-N-(4-pyridinyl)]amino-pyrrol-2-carboxaldehyde (8 g) in 100ml of 2-propanol was added sodium borohydride (3 g) as a powder. Afterstirring two hours at ambient temperature the reaction mixture wasstirred with 500 ml of water and extracted with ethyl acetate-ether. Theorganic extract was washed with water and saturated sodium chloridesolution and thereafter dried over anhydrous magnesium sulfate, filteredand evaporated to 7.6 g of an oil. This oil was purified byhigh-pressure liquid chromatography (silica, 5% methanol in ethylacetate) to give 6.2 g of a solid, mp 145°-148° C. Four gram portion wasrecrystallized from 2-propanol/petroleum ether to give 2.3 g ofcrystals, mp 150°-151° C.

Analysis Calculated for C₁₁ H₁₃ N₃ O: 65.00% C, 6.45% H, 20.68% N,Found: 64:92% C, 6.51% H, 20.73% N.

EXAMPLE 33 N-(2-Methoxymethyl-1H-pyrrol-1-yl)-N-methyl-4-pyridinamineoxalate

A solution of 1-[[N-methyl-N-(4-pyridinyl)amino]-1H-pyrrole-2-methanol(3.5 g) in 20 ml of dimethylformamide was added to a stirred suspensioncontaining 0.8 g of sodium hydride in 5 ml of dimethylformamide. Afterthe anion formation the reaction mixture was cooled with ice and asolution of dimethyl sulfate (2.5 g) in 5 ml of dimethylformamide wasslowly added. After one hour the reaction mixture was stirred with icewater and extracted with ethyl acetate. The organic extract was washedwith water and saturated sodium chloride solution, and thereafter driedover anhydrous magnesium sulfate, filtered and evaporated to 6 g of anoil. This oil was purified by flash chromatography (silica, 5% methanolin ethyl acetate) to give 3.2 g of an oil. This oil was distilled viaKugelrohr to give 2.5 g of an oil, b.p. 150°-160° C. @ 0.01 mm. This oilwas converted to the oxalate salt in 25 ml of warm 2-propanol to giveupon cooling 3.4 g of crystals, d 157°-158° C.

Analysis Calculated for C₁₂ H₁₅ N₃ O.C₂ H₂ O₄ : 54.71% C, 5.58% H,13.68% N, Found: 54.45% C, 5.58% H, 13.53% N.

EXAMPLE 34N-(2-Formyl-1H-pyrrol-1-yl)-N-(2,3,5,6-tetrachloro-4-pyridinyl)-carbamicacid ethyl ester

A solution of (2-formyl-1H-pyrrol-1-yl)-carbamic acid, ethyl ester (13g) in 60 ml of dimethylformamide was slowly added to a stirredsuspension of 3.3 g of sodium hydride in 5 ml of cold dimethylformamide.After the anion formation a solution of pentachloropyridine (21 g) in 50ml of dimethylformamide and 85 ml of tetrahydrofuran was slowly added.After stirring cold for one hour, the reaction mixture was stirred with800 ml of cold water and extracted with ethyl acetate. The organicextract was washed with water and saturated sodium chloride solution andthereafter dried over anhydrous magnesium sulfate, filtered andevaporated to 35 g of an oil. This material was purified by flashchromatography (silica, 15% ethyl acetate in hexanes) to give a total of22 g of the product as a solid. One supersaturated fraction yielded 7 gof pure product as a precipitate, mp 128°-129° C.

Analysis Calculated for C₁₃ H₉ Cl₄ N₃ O₃ : 39.32% C, 2.28% H, 10.59% N,Found: 39.06% C, 2.35% H, 10.61% N.

We claim:
 1. A compound of the formula ##STR26## where R is H,loweralkyl, halogen, cyano, loweralkanoyl, arylloweralkanoyl, aroyl,--CH(OH)r₁, --C(OH)r₁ r₂, or --CH₂ Or₂ where r₁ is H, loweralkyl,arylloweralkyl or aryl and r₂ is loweralkyl; R₁ is H, loweralkyl,arylloweralkyl, phenyl, nitrophenyl, cyanophenyl, trifluoromethylphenyl,aminophenyl, loweralkanoylaminophenyl, loweralkoxycarbonyl,arylloweralkoxycarbonyl, aryloxycarbonyl, loweralkylaminocarbonyl,arylloweralkylaminocarbonyl, arylaminocarbonyl, alkanoyl,arylloweralkanoyl, aroyl, alkenoyl or alkynoyl; and R₂ is H, NO₂, NH₂,halogen, loweralkanoylamino, arylloweralkanoylamino, aroylamino orloweralkyl, or R₂ as a whole is a combination of 2, 3 or 4 halogenatoms; or pharmaceutically acceptable acid addition salt thereof.
 2. Thecompound as defined in claim 1 where R₂ is H.
 3. The compound as definedin claim 1 where R₁ is H, loweralkyl or arylloweralkyl.
 4. The compoundas defined in claim 1 where R is H, loweralkyl, halogen, loweralkanoylor --CH(OH)r₁ where r₁ is H or loweralkyl.
 5. The compound as defined inclaim 2 where R₁ is H, loweralkyl or arylloweralkyl, and R is H,loweralkyl, halogen, loweralkanoyl or CH(OH)r₁, r₁ being H orloweralkyl.
 6. The compound as defined in claim 1, which isN-(4-pyridinyl)-N-(1H-pyrrol-1-yl)-N'-methylurea.
 7. The compound asdefined in claim 1, which is N-(4-pyridinyl)-N-(1H-pyrrol-1-yl)carbamicacid ethyl ester.
 8. The compound as defined in claim 1, which isN-(4-pyridinyl)-N-(1H-pyrrol-1-yl)-propanamide.
 9. The compound asdefined in claim 1, which isN-(4-pyridinyl)-N-(1H-pyrrol-1-yl)-linoleamide.
 10. The compound asdefined in claim 1, which is3,4-dimethoxy-N-(4-pyridinyl)-N-(1-H-pyrrol-1-yl)phenylacetamide. 11.The compound as defined in claim 1, which isN-[3-[4-[[N-methyl-N-(1H-pyrrol-1-yl)]-amino]]pyridinyl]formamide. 12.The compound as defined in claim 1, which isN-(2-chloro-1H-pyrrol-1-yl)-N-(4-pyridinyl)carbamic acid ethyl ester.13. The compound as defined in claim 1, which isN-(2-chloro-1H-pyrrol-1-yl)-N-(4-pyridinly)-3,4-dimethoxyphenylacetamide.14. The compound as defined in claim 1, wherein R₁ is methyl, which isα-methyl-1-[[N-(4-pyridinyl)-N-methyl]-amino]-1H-pyrrole-2-methanol. 15.The compound as defined in claim 1, which isN-(2-Chloro-1H-pyrrol-1-yl)-N-(4-pyridyl)-linoleamide 2-naphthalenesulfonate.
 16. The compound as defined in claim 1, which isα-Ethyl-1[(N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol. 17.The compound as defined in claim 1, which isαPropyl-1-[[N-(4-pyridinyl)-N-methyl]amino]-1H-pyrrole-2-methanol. 18.The compound as defined in claim 1, which is1-[[N-Methyl-N-(4-pyridinyl) amino]-1H-pyrrole-2-methanol.
 19. Thecompound as defined in claim 1, which isN-(2-Formyl-1H-pyrrol-1-yl)-N-(2,3,5,6-tetrachloro-4-pyridinyl)-carbamic acid ethyl ester.
 20. Apharmaceutical composition which comprises an effective memory enhancingamount of a compound defined in claim 1 in a mixture with apharmaceutically acceptable carrier or diluent.
 21. A method of treatinga patient in need of memory enhancement which comprises administering tothe patient an effective memory enhancing amount of a compound definedin claim 1.